tbuckley/cabot-search huggingface dataset:
Abstract 3673: Plk1 phosphorylation of PHGDH to regulate serine metabolism
Authors: Xiongjian Rao, Derek B. Allison, Robert M. Flight, Yuanyuan Wu, Timothy Scott, Daheng He, RuiXing Wang, Zhiguo Li, Chaohao Li, Yifan Kong, Fengyi Mao, Chi Wang, Richard M. Higashi, Andrew N. Lane, Hunter NB Moseley, Xiaoqi Liu
Journal: Cancer Research (2023)

Abstract Polo-like kinase 1 (Plk1) has been reported to be highly expressed in most tumors, especially in advanced tumors, while how Plk1 elevation benefits tumor growth remains elusive. Metabolic reprogramming is one of the hallmarks of cancer, but how the tumors fully take advantage of deregulated metabolism is an enigma. Here, we found that Plk1 could divert serine metabolism from de novo synthesis to exogenous uptake by regulating PHGDH (phosphoglycerate dehydrogenase), the first rate-limiting enzyme of de novo serine biosynthesis. We show that PHGDH is phosphorylated by Plk1 at a cluster site (S512, S513, S517) and that Plk1-associated phosphorylation of PHGDH results in its protein degradation, thus reduced de novo serine biosynthesis. As a compensatory response, cells with an elevated level of Plk1 significantly increase the uptake of serine to produce more sphingosines, which are pivotal metabolites for the growth of cancer cells. Our finding may provide guidance on how to target de novo biosynthesis of serine, serine uptake or sphingosine metabolism to treat advanced prostate cancer. Citation Format: Xiongjian Rao, Derek B. Allison, Robert M. Flight, Yuanyuan Wu, Timothy Scott, Daheng He, RuiXing Wang, Zhiguo Li, Chaohao Li, Yifan Kong, Fengyi Mao, Chi Wang, Richard M. Higashi, Andrew N. Lane, Hunter NB Moseley, Xiaoqi Liu. Plk1 phosphorylation of PHGDH to regulate serine metabolism. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3673.
Abstract 834: Synergistic effect of bacterial ghosts loaded with belinostat and betaine nano-emulsion: A potential treatment strategy for breast cancer
Authors: Sara H. Deghedy, Hoda E. Mahmoud, Ahmed A. Hussein, Mohammed A. El-Kholy, Passent M. Gaafar, Mai M. Ali, Ahmed S. Sultan
Journal: Cancer Research (2023)

Abstract Breast cancer resembles the second-highest incidence rate of cancers worldwide with highly remarkable incidence and mortality rates. Recently, the main target behind the current study is to reduce the toxicity along with targeted delivery of different drugs separately and simultaneously to enhance the treatment options for breast cancer. A promising strategy for overcoming poor drug delivery is to recruit the evacuated bacterial cells which are known as Bacterial Ghosts (BGs) for drug delivery. The present study focused on formulating a new complex delivery system using a highly purified and safety-confirmed BGs of Salmonella Typhimurium ATCC 1403 strain loaded with class II HDACI (Belinostat) associated with nano-emulsion droplets of constant and non-toxic natural compound (Betaine), a glycine with three additional methyl groups. The formulated new complex delivery system of BGs was tested on two breast cancer cell lines, ER-positive ZR-75-1 and TNBC, MDA-MB-231 respectively. Using WST-1 proliferation assay, our data reports a combination index (CI) &amp;lt;1 indicating synergistic effect between Betaine nano-emulsion at low concentrations with Poly dispersity index less than 0.5 and BGs loaded with Belinostat per constant count of BGs CFU/ml. In comparison with treatment of either Betaine or Belinostat alone, the viability inhibition and apoptosis induction of both tested MDA-MB-231 and ZR-75-1 cells were amplified in the combined treatment of 72 hours. Furthermore, the achieved delivery showed a significant downregulated expression of angiogenesis-related markers such as VEGF and TSP-1 at concentrations of 1-mM Betaine nano-emulsion and 0.2-µM Belinostat after 24 hours of treatment. In conclusion, the proposed study introduced a new formulated delivery system of BGs with synergistic mechanistic effect of two different anti-cancer compounds as a promising strategy to inhibit breast cancer cell lines proliferation and angiogenesis. Citation Format: Sara H. Deghedy, Hoda E. Mahmoud, Ahmed A. Hussein, Mohammed A. El-Kholy, Passent M. Gaafar, Mai M. Ali, Ahmed S. Sultan. Synergistic effect of bacterial ghosts loaded with belinostat and betaine nano-emulsion: A potential treatment strategy for breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 834.
Abstract 1349: Exploring CD63 as a targetable mediator of the pro-tumorigenic tissue microenvironment in HNSCC
Authors: Elisabeth B. Dingendorf, Michael C. Stoffel, Dahlia L. Kittel, Glen Kristiansen, Tristan Lerbs
Journal: Cancer Research (2023)

Abstract Introduction: Head and neck squamous cell carcinoma (HNSCC) is one of the ten most common cancer types worldwide - ranked on the sixth position with 560,000 new diagnoses and 270,000 deaths in 2020. The survival could be increased only slightly over the past decades and in addition the incidence of HNSCC continues to rise. In this study, we investigated the role of the tetraspanin CD63 during cancer progression. Methods: First, we performed survival analyses with available statistics from data bases to correlate CD63 and survival. Then, we established a 20-marker spectral FACS panel to identify different fibroblast subpopulations in patient tissue. Upon receiving patient consent, fresh HNSCC tissue was received from surgical tumor resections at the University Hospital of Bonn. We mechanically and enzymatically digested and purified the tissue of ten patients to create single-cell suspensions. After staining, the cells were measured on a Sony ID7000 Spectral Analyzer and interpreted with FlowJo. To identify whether CD63 on fibroblasts affects the differentiation of macrophages in vitro, we isolated primary fibroblasts and monocytes from HNSCC patients and deleted CD63 in fibroblasts by CRISPR-Cas9. Thereafter, we co-incubated fibroblasts (without and with the CD63-Knockout) and macrophages over ten days in M-CSF containing medium, and measured the expression of M1 and M2 markers through flow cytometry. Results: First, correlating CD63 gene expression with the patient outcome showed that CD63 correlated with a decreased survival. Then, analyzing fresh tumor specimens with the multicolor panel showed an increase of CD63 expression in different fibroblast subpopulations in the tumor specimens, e. g. CD9+ CD34+ CD63+ CD90+ fibroblasts increased more than eightfold. Investigating potential mechanisms, by which CD63 expression on fibroblasts affects tumor progression, deleting CD63 steered macrophages towards the pro-inflammatory M1 phenotype. Conclusion: This study demonstrates that HNSCC increases CD63 expression in different fibroblast populations and that deleting CD63 on fibroblasts can steer macrophages towards the pro-inflammatory phenotype, thereby suggesting a rationale for testing CD63 as a therapeutic target. Citation Format: Elisabeth B. Dingendorf, Michael C. Stoffel, Dahlia L. Kittel, Glen Kristiansen, Tristan Lerbs. Exploring CD63 as a targetable mediator of the pro-tumorigenic tissue microenvironment in HNSCC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1349.
Abstract 1976: Lung cancer screening disparities in Southeastern U.S
Authors: Desiree A. Rivers
Journal: Cancer Research (2023)

Abstract Purpose: In Alabama, lung cancer is the leading cause of cancer death. High lung cancer incidence and mortality rates are attributed to high smoking rates among underserved, low income, and rural populations. Rural residents in Alabama tend to be older, engage in risky health behaviors, and have lower adherence to preventive care than do their urban and suburban counterparts. Disparities in mortality rates between rural and urban areas are particularly large for lung cancer. It can be explained by increased tobacco use and the preponderance of late-stage diagnoses following the lack of uptake of LCS. Therefore, we examined factors associated with LCS uptake among patients who were referred to screening at University of Alabama at Birmingham (UAB) from 2015-2020. Method: A retrospective cohort of individuals seen at UAB who were eligible for lung cancer screening from 01/01/2015 and 12/31/2020 was used to define the cohort. Included individuals were 55-80 years old, without diagnostic codes for lung cancer (ICD9 162.9 or ICD10 C34.90 within the past 10 years), and a history of smoking: Patient demographic variables included Age; Sex; Race/Ethnicity; distance from UAB and RUCA codes. Chi-square tests and Student t-tests was used to compare screening uptake across patient demographic and clinical variables. We used bivariate analyses to determine significant predictors of lung cancer screening uptake at UAB. Results: 67355 were identified as eligible for LCS of whom 1147 were screened, 16 individuals were not AL residents and therefore were not included in further analysis. Of those 1129 individuals screened, mean age was 67.02, male (54.92%) and Non-Hispanic White (57.77%). When compared to those who were not screened(97.86%), those screened were more likely to have live in an urbanized area (2.14%). Additionally, when compared to those who were not screened (48.16 mi), those screened were more likely to live closer to UAB (28.67 mi). Conclusion: LCS has not reached all subgroups; additional targeted efforts are essential to increase lung cancer screening uptake. Citation Format: Desiree A. Rivers. Lung cancer screening disparities in Southeastern U.S [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1976.
Abstract 3702: Serine promotes aggressive phenotype in renal cancer
Authors: Suman Karki, Anirban Kundu, Garret Brinkley, Hyeyoung Nam, Kayla Goliwas, Jessy Deshane, Sunil Sudarshan
Journal: Cancer Research (2023)

Abstract Tumor cells are known to have increased demand for nutrients to support proliferation. Among the most highly utilized nutrients by tumor cells are nonessential amino acids (NEAAs). While the role of NEAAs in supporting tumor growth is well-established, their role in supporting aggressive phenotypes such as migration and invasion is poorly understood. Yet, the major cause of morbidity from malignancies such as renal cell carcinoma (RCC) is metastasis. Through an unbiased approach, we assayed the role of NEAAs in promoting the migration of RCC cells. We demonstrate that exogenous serine and glutamine are essential and sufficient to support aggressive phenotypes in RCC. Moreover, the availability of both NEAAs is critical for the expression of the proinvasive transcription factor SNAIL. Our data converge on the role of these two NEAAs in supporting the translation of this factor. Perturbations that limit the availability and/or synthesis of either result in translational reprogramming through the integrated stress response (ISR) that leads to loss of SNAIL1 expression and attenuates aggressive phenotypes. Our findings associate nutrient status to the ISR including ER stress. Collectively, our study highlights new insights for NEAA metabolism in supporting aggressive tumor phenotypes and could reveal novel approaches to mitigate metastasis by targeting NEAA availability and/or utilization. Citation Format: Suman Karki, Anirban Kundu, Garret Brinkley, Hyeyoung Nam, Kayla Goliwas, Jessy Deshane, Sunil Sudarshan. Serine promotes aggressive phenotype in renal cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3702.
Abstract 3720: Cysteine palmitoylation of astrocyte elevated gene-1/Metadherin (AEG-1/MTDH) regulates its biological and immunological activity
Authors: Maria Del Carmen Camarena, Garrison Komaniecki, Debashri Manna, Rachel Mendoza, Mark A. Subler, Jolene J. Windle, Mikhail G. Dozmorov, Hening Lin, Devanand Sarkar
Journal: Cancer Research (2023)

Abstract Non-alcoholic steatohepatitis (NASH) is a major risk factor for hepatocellular carcinoma (HCC). Astrocyte elevated gene-1/Metadherin (AEG-1/MTDH) augments steatosis, inflammation, and tumorigenesis, thereby promoting the whole spectrum of this disease process. Targeting AEG-1 is a potential interventional strategy for NASH and HCC. Thus, proper understanding of the regulation of this molecule is essential. We found that AEG-1 is palmitoylated at residue Cysteine75 (Cys75). Mutation of Cys75 to Serine (Ser) completely abolished AEG-1 palmitoylation.Systematic knockdown studies identified zinc finger DHHC-type palmitoyltransferase 6 (ZDHHC6) as the palmitoyltransferase catalyzing the process. To obtain insight into how palmitoylation regulates AEG-1 function, we generated a knock-in mouse by CRISPR/Cas9 in which Cys75 of AEG-1 was mutated to Ser (AEG-1-C75S). No developmental or anatomical abnormality was observed between AEG-1-wild type (AEG-1-WT) and AEG-1-C75S littermates. However, global gene expression analysis by RNA-sequencing unraveled that signaling pathways and upstream regulators, which contribute to cell proliferation, motility, inflammation,angiogenesis, and lipid accumulation, are activated in AEG-1-C75S hepatocytes compared toAEG-1-WT. Feeding these mice with high fat/high sugar diet for 20 weeks showed accumulation of T-regulatory cells and exhausted CD8 T-cells in the livers of AEG-1-C75S mice vs AEG-1-WT, and only in females, suggesting that inhibition of AEG-1 palmitoylation creates an immunosuppressive milieu favoring tumorigenesis. Collectively, these findings suggest that AEG-1-C75S functions as dominant positive, and palmitoylation restricts oncogenic and NASH-promoting functions of AEG-1. Studies are ongoing to unravel the mechanism by which palmitoylation restricts AEG-1 function, and to understand the sex-specific immune-modulatory role of AEG-1 palmitoylation in hepatocarcinogenesis. Citation Format: Maria Del Carmen Camarena, Garrison Komaniecki, Debashri Manna, Rachel Mendoza, Mark A. Subler, Jolene J. Windle, Mikhail G. Dozmorov, Hening Lin, Devanand Sarkar. Cysteine palmitoylation of astrocyte elevated gene-1/Metadherin (AEG-1/MTDH) regulates its biological and immunological activity. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3720.
Abstract 2525: Analyzing the role of MDMX for regulating cell death in prostate cancer cells
Authors: Ahmed Alsarrani, Umamaheswari Natarajan, Samia Alsubhi, Amal Alzahrani, Appu Rathinavelu
Journal: Cancer Research (2023)

Abstract Prostate cancer (PCa) is the most prominent cancer type and the second leading cause of cancer death among men in the USA. The five-year survival rate for localized PCa is 98% but drops to 31% when PCa spreads to different parts of the body. Various treatment strategies that can induce cell death through different mechanisms are used while treating cancers. In recent years, necroptosis has been established as one of the effective mechanisms of inducing cell death in cancers. Necroptosis can be identified as a regulated form of cell death that can occur independently of executioner caspases. Despite numerous studies on the effects of necroptosis in cancer, it’s role on PCa has not been fully elucidated. In this study, we have evaluated the role of MDMX, a proto-oncogene involved in the negative regulation of p53, in causing cell death through p53-independent mechanisms. We have observed that inhibition of MDMX decreased the cell viability of LNCaP cells in response to 20 µM of NSC (NSC-207895), a MDMX specific inhibitor treatment, in a concentration-dependent manner. MDMX inhibition appears to induce necroptosis in LNCaP prostate cancer cells by elevating the expression of receptor-interacting protein kinase 1 (RIP1), which is a key element of the necroptotic pathway. In general, the necroptosis pathway can trigger two opposing mechanisms in cancer where it can promote tumor migration and metastasis on one hand and can also act as a defensive mechanism on the other hand when apoptosis is disrupted. To further assess the effect of MDMX on cell migration, the LNCaP cells were treated with 20 µM of NSC, which effectively blocked the cancer cell migration for up to 48 h, which was confirmed using the scratch assay. Interestingly, NSC treatment also reduced the expression of Vascular Endothelial Growth Factor A (VEGFA), which is one of the main markers for angiogenesis. Our results show that the p53-independent mechanisms that are activated following MDMX inhibition can regulate both cancer cell migration and angiogenesis. MDMX also seemed to be involved in regulating PCa cell survival through necroptosis. The outcomes of our experiments provide additional knowledge and strategies for making an accurate prognosis and choosing the most suitable therapeutic strategies for offering effective treatments for MDMX-positive PCa. (This research was supported by the Royal Dames of Cancer Research Inc. Ft. Lauderdale, Florida) Citation Format: Ahmed Alsarrani, Umamaheswari Natarajan, Samia Alsubhi, Amal Alzahrani, Appu Rathinavelu. Analyzing the role of MDMX for regulating cell death in prostate cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2525.
Abstract 3681: c-MAF-driven metabolic reprogramming mediates H3K27 hyperacetylation to regulate super enhancer-associated genes
Authors: Phyllis SY Chong, Sze Lynn Julia Lim, Jianbiao Zhou, Aaron Chung Yong Leow, Wee Joo Chng
Journal: Cancer Research (2023)

Abstract Overexpression of transcription factor c-MAF is found in about 50% of multiple myeloma cases, and associated with the prognostically unfavorable t(14;16) translocation subtype. Genetic alterations can modify the epigenome through metabolite availability that act as substrates in histone modifications, but how this translates into specificities in gene regulation is unclear. Here, we report a novel involvement of c-MAF in metabolically-driven histone acetylation, including the superenhancer mark H3K27ac, through altering acetyl-CoA metabolism. To sustain high levels of acetylation, c-MAF acquired the metabolic flexibility to utilize glutamine in addition to glucose, feeding into the tricarboxylic acid (TCA) cycle as acetyl-CoA sources. Loss-of-function studies indicated that c-MAF is important for citrate-derived acetyl-CoA and H3K27ac levels through metabolic enzymes citrate synthase (CS) and ATP-citrate lyase (ACLY). Furthermore, blocking citrate export from mitochondrial via CRISPR/Cas9 targeting of SLC25A1 reproduced the reductions in H3K27ac. Silencing of c-MAF also displayed defective mitochondrial oxidative phosphorylation attributed to reduced metabolic flux through TCA cycle and downregulation of electron transport chain complex I/II expression, without affecting mitochondrial DNA content. To identify c-MAF-regulated superenhancer genes, we overlapped our previously published H3K27ac ChIP-seq dataset on t(14;16) MM cell lines with c-MAF RNA-seq data. We found signal enrichment of H3K27ac at ZC3H3 locus responsible for its transcriptional upregulation, and knockdown of ZC3H3 inhibited cell growth specifically in the t(14;16) subtype. Altogether, we demonstrated a non-canonical c-MAF role in epigenetics that is connected to its altered metabolic state, and suggest metabolic disruptions as a new therapeutic direction in t(14;16) myeloma. Citation Format: Phyllis SY Chong, Sze Lynn Julia Lim, Jianbiao Zhou, Aaron Chung Yong Leow, Wee Joo Chng. c-MAF-driven metabolic reprogramming mediates H3K27 hyperacetylation to regulate super enhancer-associated genes. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3681.
Abstract 3686: Blocking fatty acid oxidation suggests a potential new therapeutic approach for pancreatic cancer
Authors: Sang M. Woo, Sung-Sik Han, Ho Lee, Soo-Youl Kim
Journal: Cancer Research (2023)

Abstract Background: Glycolysis is known as the main pathway for ATP production in cancer cells. However, in pancreatic ductal adenocarcinoma (PDAC) cells, glucose deprivation for 24 h did not reduce ATP levels, whereas it suppressed lactate production. We found that ATP production in PDAC cells critically depended on fatty acid oxidation (FAO) while normal cells showed no dependency on fatty acid. Therefore, FAO inhibition significantly decrease oxygen consumption rate as well as ATP production only in cancer cells. Methods: To test whether cancer depends on fatty acid for energy metabolism, high- or low-fat diet was tested in spontaneous PDAC cancer model (KPC mouse: Kras(G12D)/p53(R172H)/Pdx1-Cre model). To test whether FAO is absolute requirement for ATP production in cancer, overall survival (OS) was monitored in KPC mice by crossbreeding with FAO gene knock out mice. Results: First, the effects of calorie balanced high- or low-fat diets were tested to determine whether cancer growth is modulated by fatty acid instead of calories. A low-fat diet caused a 70 % decrease in pancreatic preneoplastic lesions accompanying decrease of body weight 20% compared with the control, whereas high-fat diet caused a 2-fold increase in preneoplastic lesions accompanied with 25% increase of body mass index in Kras(G12D)/p53(R172H)/Pdx1-Cre model (KPC model; spontaneous PDAC model). Second, the effect of FAO gene knock down was tested to determine whether OS is increased in KPC model. The crossbreeding of FAO gene knockout (+/-) and KPC mice resulted in 2-fold increase of OS. Conclusions: The two results suggest that controlling obesity by diet as well as targeting FAO can enhance anti-cancer effect of cancer therapeutics including conventional anti-cancer drug or immune-oncology drug. Clinical Trial Identification: IND for PDAC therapy with drugs targeting FAO will be submitted in 2022. Legal Entity Responsible for the Study: This study is legally under review by IRB in National Cancer Center, Korea, and sponsored by National Research Foundation of Korea (NRF) and NCC-Bio Co. Funding: Funding source: Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Science and ICT (NRF-2019M3A9G1104345) Citation Format: Sang M. Woo, Sung-Sik Han, Ho Lee, Soo-Youl Kim. Blocking fatty acid oxidation suggests a potential new therapeutic approach for pancreatic cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3686.